Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)-China Extension

NCT ID: NCT04934722

Last Updated: 2025-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 186 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-25
• Study Completion Date: 2025-09-10

Brief Summary

This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT in Chinese participants with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to 1) radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) and 2) overall survival (OS). As of Amendment 4, the study is being stopped for futility. All the prespecified interim analysis after interim analysis (IA1) and final analysis of the study described the statistical analysis plan (SAP) will not be performed. Safety analysis will be performed at the end of the study; there will be no further analyses for efficacy and electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the IA1 cutoff date. All study participants will stop ongoing treatment with pembrolizumab/placebo. Exceptions may be requested for study participants who, in the assessment of their study physician, are benefitting from the combination of enzalutamide and pembrolizumab, after consulting with the Sponsor. All other study participants should be discontinued from study and be offered standard of care (SOC) treatment as deemed necessary by the Investigator. If enzalutamide as SOC is not accessible off study to the participant, central sourcing may continue. As of Amendment 04, disease progression will no longer be centrally verified, participants will only be assessed locally. As of Amendment 4, Second Course treatment is not an option for participants. There are currently no participants in the Second Course Phase.

Detailed Description

The China extension study will include participants previously enrolled in China in the global study for MK-3475-991 (NCT04191096) plus those enrolled during the China extension enrollment period. A total of approximately 186 Chinese participants will be enrolled.

Conditions

Metastatic Hormone-Sensitive Prostate Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Pembrolizumab + Enzalutamide + ADT

Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab intravenously (IV) every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a luteinizing-hormone releasing hormone (LHRH) agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: BIOLOGICAL

Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.

Enzalutamide

Intervention Type: DRUG

Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.

Androgen Deprivation Therapy (ADT)

Intervention Type: DRUG

Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.

Placebo + Enzalutamide + ADT

Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a LHRH agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Group Type: PLACEBO_COMPARATOR

Enzalutamide

Intervention Type: DRUG

Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.

Androgen Deprivation Therapy (ADT)

Intervention Type: DRUG

Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.

Placebo

Intervention Type: OTHER

Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.

Interventions

Pembrolizumab

Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.

Intervention Type: BIOLOGICAL

Enzalutamide

Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.

Intervention Type: DRUG

Androgen Deprivation Therapy (ADT)

Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.

Intervention Type: DRUG

Placebo

Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.

Intervention Type: OTHER

Other Intervention Names

KEYTRUDA®; MK-3475; XTANDI®

Eligibility Criteria

Inclusion Criteria

• Male participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
• Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
• Willing to maintain continuous Androgen Deprivation Therapy (ADT) with a luteinizing-hormone releasing hormone (LHRH) agonists or antagonists during study treatment or have a history of bilateral orchiectomy
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
• Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
• Has adequate organ function
• Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). Participants with bone only or bone predominant disease may provide a bone biopsy sample
• Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
• Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex

Exclusion Criteria

• Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications
• Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
• Has an active infection (including tuberculosis) requiring systemic therapy
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has a history of seizure or any condition that may predispose to seizure
• Has a history of loss of consciousness within 12 months of screening
• Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
• Has hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit
• Has a history of clinically significant ventricular arrhythmias
• Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
• Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for >39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
• Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
• Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
• Has received a live vaccine within 30 days prior to randomization
• Has a "superscan" bone scan
• Has had an allogenic tissue/solid organ transplant
• Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions:

1. Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel

2. May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization

3. For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization

4. Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

Peking University First Hospital ( Site 0800)

Beijing, Beijing Municipality, China

Beijing Cancer Hospital ( Site 0802)

Beijing, Beijing Municipality, China

Chongqing Cancer Hospital ( Site 0815)

Chongqing, Chongqing Municipality, China

The First Affiliated Hospital of Xiamen University (Site 0816)

Xiamen, Fujian, China

Sun Yat-Sen University Cancer Center ( Site 0825)

Guangzhou, Guangdong, China

The First Affiliated Hospital of Guangzhou Medical University-Urology ( Site 0638)

Guangzhou, Guangdong, China

Sun Yat Sen Memorial Hospital (Site # 0819)

Guangzhou, Guangdong, China

Southern Medical University Nanfang Hospital ( Site 0838)

Guangzhou, Guangdong, China

Harbin Medical University Cancer Hospital ( Site 0822)

Harbin, Heilongjiang, China

Henan Cancer Hospital ( Site 0818)

Zhengzhou, Henan, China

Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site 0829)

Wuhan, Hubei, China

Hubei Cancer Hospital ( Site 0833)

Wuhan, Hubei, China

Hunan Cancer Hospital ( Site 0817)

Changsha, Hunan, China

Nanjing Drum Tower Hospital ( Site 0811)

Nanjing, Jiangsu, China

The First Affiliated Hospital of Nanchang University ( Site 0821)

Nanchang, Jiangxi, China

The Second Affiliated Hosp of Xi'an Jiaotong Univ College of Medicine ( Site 0831)

Xi'an, Shaanxi, China

Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0807 )

Shanghai, Shanghai Municipality, China

The first affiliated Hospital of Xi an Jiaotong University ( Site # 0812)

Xi’an, Shanxi, China

Tianjin Medical University Cancer Institute & Hospital ( Site 0804 )

Tianjin, Tianjin Municipality, China

2nd Affil Hosp of Zhejiang University College of Medicine ( Site 0808)

Hangzhou, Zhejiang, China

The 1st Affil Hosp of College of Medicine, Zhejiang Univ ( Site 0830)

Hangzhou, Zhejiang, China

Zhejiang Provincial People's Hospital ( Site 0809)

Hangzhou, Zhejiang, China

Ningbo First Hospital-Urology (0835)

Ningbo, Zhejiang, China

The First Affiliated Hospital of Wenzhou Medical University ( Site 0834)

Wenzhou, Zhejiang, China

Countries

China

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.merckclinicaltrials.com

Merck Clinical Trials Information

Other Identifiers

MK-3475-991 China Extension

Identifier Type: OTHER

Identifier Source: secondary_id

KEYNOTE-991

Identifier Type: OTHER

Identifier Source: secondary_id

jRCT2080225171

Identifier Type: REGISTRY

Identifier Source: secondary_id

3475-991 China Extension

Identifier Type: -

Identifier Source: org_study_id